JPS6254119B2 - - Google Patents

Abstract

Novel DELTA 4,9-gonadiene-21-ol-3,20-diones of the formula <IMAGE> I wherein X is selected from the group consisting of hydrogen and tritium, R1 is alkyl of 1 to 3 carbon atoms, R2 is alkyl of 1 to 12 carbon atoms and R3 is alkyl of 1 to 4 carbon atoms in the form of 21R or 21S epimers or mixtures thereof having progestomimetic and antiestrogenic properties, their preparation and novel intermediates.

Description

[Detailed description of the invention]

The present invention provides novel 3,20-dioxo-4,9-
The present invention relates to diene-21-hydroxyl steroid derivatives, their preparation, their use as medicaments and pharmaceutical compositions containing them. The subject of the invention is the following formula (Here, X represents a hydrogen or tritium atom, R ₁ represents an alkyl group containing 1 to 3 carbon atoms, R ₂ represents an alkyl group containing 1 to 12 carbon atoms, and R ₃ represents an alkyl group containing 1 to 4 carbon atoms) or in the form of a 21R or 21S epimer or a mixture of these epimers. Among the compounds of the formula, mention may be made in particular of those in which X represents a hydrogen atom. R ₁ preferably represents a methyl or ethyl group. _R2 is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n
- represents a pentyl, n-hexyl, 2-methylpentyl, 2,3-dimethylbutyl, n-octyl or 2,2-dimethylhexyl group. R ₃ preferably represents a methyl, ethyl or n-propyl group. A subject of the invention is, in particular, compounds of the formula in which R ₁ represents a methyl group and are in the form of a 21R or 21S epimer, respectively or a mixture of these epimers, R ₂ represents a methyl group, and the 21R or 21S epimer or in the form of a mixture of these epimers, as well as compounds of the formula in which R ₃ represents a methyl group and are in the form of a 21R or 21S epimer, respectively, or a mixture of these epimers. More particularly, the subject of the invention is a compound whose preparation is shown in the experimental part, the hydroxyl
Compounds in the form of each of the 21R and 21S epimers or a mixture of these epimers, especially the
Compounds in which the 21 position is in the S configuration (A in the following examples)
). Compounds of the formula in which X represents a hydrogen atom exhibit valuable pharmacological properties, in particular significant progestin-like and antiestrogen-like activity, as shown by the test results presented further in the experimental section.
These properties make the compounds of formula suitable for use as pituitary suppressive progestative agents with anti-LH predominance or as anti-estrogenic substances. However, these symptoms include dysmenorrhea, infertility,
It is used to treat ovarian dystrophies that make the ovaries inactive, to treat tumors of the breast or uterus, and as a contraceptive. The subject of the invention is therefore the compounds of the formula as medicaments. More particularly, the subject of the invention is compounds of the formula in which X represents a hydrogen atom, the preparation of which is further shown in the experimental section. A preferred agent of the invention is a compound referred to as A in Examples 1 or 2 below, in which the hydroxyl at position 21 is in the S configuration. The effective dosage will vary depending on the disease being treated and the route of administration. For example, it is between 10 μg and 50 mg per day of the compound of Example 1, referred to as A in the experimental section, administered orally to an adult female. Compounds of this formula can be administered orally, by the rectal route,
It is used parenterally or topically for local application to the skin and mucous membranes. They are prepared in the form of compressed tablets, coated tablets, cachets, capsules, granules, emulsions, syrups, suppositories, injectable solutions and suspensions, ointments, creams, gels and aerosol preparations. The subject of the invention is therefore pharmaceutical compositions which contain as active ingredient at least one compound of the formula in which X represents a hydrogen atom. The active ingredients include the adjuvants customary in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate,
It can be mixed with cocoa butter, aqueous or non-aqueous carriers, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents and/or preservatives. These pharmaceutical compositions can be manufactured by conventional methods. Compounds of the formula in which X represents a tritium atom generally have the same pharmacological properties as compounds of the formula in which X represents a hydrogen atom. Furthermore, these compounds, especially the S-isomer at position 21, shown in the experimental section below, have been found to be particularly effective in the uterine cytosol or in the cytoplasm of tumor cells (breast cancer) and in rats due to their specific activity.
Facilitates confirmation of the presence and location of specific receptors for progesterone in tumors caused by DMBA (9,10-dimethyl-1,2-benzanthracene). These compounds have the advantage compared to progesterone that they are not immobilized on transcortina and have an affinity for progesterone receptors that is 2 to 10 times greater than that of progesterone. The subject of the invention is therefore a compound of the formula in which X represents a tritium atom, in particular in the uterine cytosol and in the cytoplasm of tumor cells and in rats.
- To localize and confirm the specific receptor of progesterone in tumors induced by dimethyl-1,2-benzanthracene. The subject of the present invention also relates to the localization of specific receptors for progesterone, in particular in the uterine cytosol and the cytoplasm of tumor cells, and in tumors induced by 9,10-dimethyl-1,2-benzanthracene in rats. There are means to do so. A compound of the formula in which X represents a tritium atom is
It shows a specific activity of about 50 Ci/mM. These compounds have been described in many publications, e.g. JP
“Sleroids” 7 by Raynaud and D. Philibert
It can be used for the localization and quantification of the specific receptor for progesterone by the method described in the Japanese issue, pp. 89-97 (1973). The subject matter of the present invention is also a method for producing a compound of the formula in which X represents a hydrogen atom, and this production method is carried out by the following formula:
(Here, K represents a ketal group, and R ₁ , R ₂ and R ₃ have the same meanings as above) is treated with an oxidizing agent in the presence of a tertiary alcoholate, and then treated with a reducing agent. Let the following formula The compound is obtained as a mixture of 21R and 21S epimers, and the ketal group is hydrolyzed and the △5(10)/9(11) double bond system is isomerized into the △4/9 double bond system. The following equation corresponds to the action of acid hydrolysis, which can be is obtained as a mixture of 21R and 21S epimers, which can be separated into each of the epimers if desired. K preferably represents a cyclic alkyl ketal group having 2 to 4 carbon atoms, especially ethylene ketal or propylene ketal or dialkyl ketal, such as dimethyl or diethyl ketal. The oxidizing agent is preferably molecular oxygen. The tertiary alcoholate is preferably an alkali metal t-butyrate or t-amylate, such as a sodium, potassium or lithium t-butyrate or t-amylate. The reducing agent used is preferably a trialkyl phosphite, such as trimethyl or triethyl phosphite. The acid hydrolyzing agent capable of hydrolyzing the ketal group and isomerizing the Δ5(10)/9(11) double bond system to the Δ4/9 double bond system is preferably a polystyrene carrier or a styrene carrier. -A commercially available sulfonic acid resin with a divinylbenzel polymer carrier,
However, inorganic acids such as hydrochloric acid or sulfuric acid can also be used. p-Toluenesulfonic acid or peracid can also be used. The resulting epimers can be separated by standard chromatographic methods. The subject of the present invention is also a method for producing a compound of the above formula, which method comprises the following formula _A (Herein, K, R ₁ , R ₂ , R ₃ and The compound was obtained as a mixture of 21R isomer and 21S isomer, and this was treated with alkali acetate to form the following formula: was obtained as a mixture of 21R and 21S isomers, and the ketal group was hydrolyzed and △
By acting with an acid hydrolyzing agent that can isomerize the 5(10)/9(11) double bond system into a △4/9 double bond system, the following formula is obtained. The compound of _formula is obtained as a mixture of the 21R and 21S isomers, which can be separated, if desired, into each of the epimers. K preferably has the meaning given above. The strong base is preferably butyllithium and the reaction is carried out in the presence of an amine, especially N-cyclohexylisopropylamine. The strong base used may also be an alkali hydride or an alkali t-butyrate. The alkali acetate is preferably sodium or potassium acetate. The acid hydrolyzing agent capable of hydrolyzing the ketal group and isomerizing the △5(10)/9(11) double bond system to the △4/9 double bond system is one of those mentioned above. That's fine. The saponifying agent may in particular be an alkaline base, such as sodium hydroxide or potassium hydroxide. The resulting epimers can be separated by standard methods of chromatography as described above. The formula obtained during implementation of the method of the invention,
The compounds of and are new compounds, and therefore the subject of the present invention is the compounds of these formulas and as new compounds. Among the compounds of formula, especially 17α-methyl-17
Cyclic 3 of β-(2-hydroxy-1-oxopropyl)estra-5(10)・9(11)-dien-3-one
-(1,2-ethanediyl)acetal in the form of each of its hydroxyl epimers or a mixture of these epimers. Among the compounds of formula, especially 17α-methyl-17
Cyclic 3-(2-iodo-1-oxopropyl)estra-5(10)・9(11)-dien-3-one
(1,2-ethanediyl)acetal, and 17α
-Methyl-17β-(2-iodo-1-oxopropyl)estra-5(10)・9(11)-dien-3-one cyclic [6・7 ³ H]-3-(1・2-ethanediyl ) Acetals in the form of each of their iodine epimers or mixtures of these epimers. Among the compounds of formula, especially 17α-methyl-17
Cyclic 3 of β-(2-acetoxy-1-oxopropyl)estra-5(10)・9(11)-dien-3-one
-(1,2-ethanediyl)acetal, and 17
α-Methyl-17β-(2-acetoxy-1-oxopropyl)estra-5(10)・9(11)-diene-3
-one cyclic [6.7 ³ H]-3-(1.2-ethanediyl) acetals in the form of each of their acetoxyl epimers or mixtures of these epimers. Among the compounds of the formula, in particular, 17β-(2-acetoxy-1-oxopropyl)-17α-methylestra-4,9-dien-3-one, and [6,7 ³ H]-17β-(2 -acetoxy-1-oxopropyl)-17α-methylester 4,9-
Mention may be made of the dien-3-ones in the form of each of their acetoxyl epimers or a mixture of these epimers. The compounds of the formula used as starting materials for the process of the invention are generally known substances and can be prepared, for example, by the process of French Patent No. 2149302. Compounds of formula _A in which X represents a tritium atom can be prepared by the method of French Patent No. 2,374,335. The examples below are illustrative of the invention and do not limit it in any way. Example 1 17α-methyl-17β-(2-hydroxy-1-
oxopropyl)estra-4,9-diene-
3-one step A: 17α-methyl-17β-(2-hydroxy-1-oxopropyl)estra-5(10)/9(11)
-Cyclic 3-(1,2-ethanediyl)acetal of dien-3-one A solution of 907 mg of potassium t-butyrate and 0.852 cc of triethyl phosphite in 13.6 cc of dimethylformamide is bubbled with oxygen at -20°C. . While continuing to blow oxygen, 1g of 17α
-Methyl-17β-(1-oxopropyl)estra-5(10)・9(11)-dien-3-one cyclic 3
-(1,2-ethanediyl)acetal 10 c.c.
solution in dimethylformamide at −20°C.
Add slowly. Leave at -20℃ for 30 minutes, then add water and 1N hydrochloric acid to adjust the pH to 5.6. Extract 5 times with 150 c.c. of isopropyl ether. The organic phase is dried, filtered and concentrated to dryness. 1.554 g of the expected product are thus obtained, which is used as such in the next step. Step B: 17α-Methyl-17β-(2-hydroxy-1-oxopropyl)estra-4,9-dien-3-one 8 c.c. containing 510 mg of the product obtained in Step A.
750 mg Redex CF in 95° ethanol
Add (Redex CF) resin. The resulting mixture is heated to reflux for 7 hours. The resulting resin is filtered and washed with ethanol and then methylene chloride. Concentrate to dryness under reduced pressure. 474 mg of resin was obtained, which was chromatographed on silica (eluent: methylene chloride/acetone 9:
1). The fraction containing the two epimers at position 21 is isolated. These two epimers are separated by high pressure liquid chromatography. Inner diameter 6
mm, 400 mm long silica (5μ silica) column. Flow rate 160ml/hour. The solvent is methylene chloride/
Ethyl acetate (7:3). UV detector 305nm. The product with a retention time of 19 minutes is designated A. The product with a retention time of 17 minutes is designated B. The physical constants of product A are as follows. (a) NMR spectrum (CDCl ₃ ) 4-position ethylenic H 5.70ppm 13-position CH ₃ 0.84ppm 21-position H 4.33ppm, multiplet 22nd-position CH ₃ 1.27ppm and 1.38ppm (doublet) 17α-position CH ₃ 1.18ppm (b) Mass spectrum Molecular peak at 342 The physical constants of Formation B are as follows. (a) NMR spectrum (CDCl ₃ ) Ethylene H at position 4 5.70ppm CH 3 at position ₁₃ 0.81ppm H at position 21 4.38ppm, 4.50ppm, 4.61ppm,
4.73ppm, CH ₃ at 22nd position 1.26ppm, 1.37ppm CH ₃ at 17α position 1.16ppm (b) Mass spectrum Example of molecular peak at 342 2 17β-(2-hydroxy-1-oxopropyl)-17α-methylestra-4.9 -dien-3-one (isomer A and isomer B) Step B: 17α-methyl-17β-(2-iodo-1
Cyclic 3-(1,2-ethanediyl)acetal of -oxopropyl)estra-5(10).9(11)-dien-3-one (mixture of isomers) (a) Formation of enolate 11.1 cc of N- Dissolve cyclohexylisopropylamine in 145 c.c. of tetrahydrofuran, cool to -40°C, add 23.3 cc of a hexane solution of butyllithium, stir for 5 minutes,
10.3 g of 17α-methyl-17β-(1-oxopropyl)estra-5(10)·9(11)-diene-
Add 3-one cyclic 3-(1,2-ethanediyl) acetal and heat again at 40℃.
Stir for 20 minutes. (b) Formation of iodinated derivative A solution of 8.2 g of iodine dissolved in 60 c.c. of tetrahydrofuran was cooled to -50°C, the above enolate solution was added over 5 minutes, and the solution was heated to -50°C. Stir for 5 minutes and allow the solution to come to room temperature. This solution was poured onto 100 c.c. of saturated ammonium chloride solution, extracted with ether,
Washed with 10% aqueous sodium thiosulfate solution, then water, dried, and distilled to dryness under reduced pressure.
14.5 g of product is obtained and used immediately as is in the next step. Step B: 17α-methyl-17β-(2-acetoxy-1-oxopropyl)estra-5(10)/9(11)
- cyclic 3-(1,2-ethanediyl)acetal of dien-3-one (mixture of isomers) 14.9 g of the iodinated derivative obtained in step A, 29 g
of anhydrous potassium acetate and 50 c.c. of dimethylformamide are stirred at 80° C. for 1 hour under an inert atmosphere. The mixture is poured into 300 c.c. of water, extracted with ether, washed with water, dried and concentrated to dryness under reduced pressure. 11.8 g of expected product are obtained. Step C: 17β-(2-acetoxy-1-oxopropyl)-17α-methylestra-4,9-dien-3-one (mixture of isomers) 11.8 g of the product obtained above, 110 c.c. . of acetic acid and 11 c.c. of perchloric acid are dissolved under an inert atmosphere. Stir at ambient temperature for 1 hour, dilute with 400 c.c. of water, extract with methylene chloride, wash with saturated aqueous sodium bicarbonate, dry, and concentrate to dryness under reduced pressure. 12 g of product are obtained and purified by chromatography on silica, eluting with a benzene/ethyl acetate mixture (8:2).
5.6 g of product is obtained and used directly in the next step. Step D: 17β-(2-hydroxy-1-oxopropyl)-17α-methylestra-4,9-dien-3-one (isomer A and isomer B) on 8.6 g under an inert atmosphere. The product obtained is dissolved in 50 c.c. of methanol, 86 mg of potassium hydroxide is added and stirred for 5 hours at ambient temperature. Add 50 c.c. of 0.1N hydrochloric acid, extract with methylene chloride, dry, and concentrate to dryness under reduced pressure.
7.6 g of product are obtained. Chromatography on silica under pressure, eluting with a benzene/ethyl acetate mixture (8:2) gave 2.7 g of isomer B.
2.5 g of isomer A is recovered. Isomer B is recrystallized from ether and then from ethanol to give 1.3 g of a product melting at 190°C. Analysis Calculation: C% 77.15 H% 8.83 Actual measurement: 77.2 9.0 [α] ²⁰ _D = -345° ± 4.5° (cc = 1%, CHCl ₃ ) NMR spectrum (CDCl ₃ ) Hydrogen at 2-position of propyl: 4.58 ppm Quadruple line, J=
7 Hydrogen in the 3-position of propyl: 1.27-1.38 ppm Hydrogen in the 17α-position CH ₃ : 1.17 ppm Hydrogen in the 18-position CH ₃ : 0.82 ppm Isomer A was recrystallized from ether, giving 1.2 g of product melting at 122 °C. obtain. Analysis Calculation: C% 77.15 H% 8.83 Actual measurement: 77.2 9.1 [α] ²⁰ _D = -208° ± 3° (C = 1%, CHCl ₃ ) NMR spectrum (CDCl ₃ ) Propyl 2-position hydrogen: 4.2-4.67 Hydrogen at CH ₃ at quartet 17α position: 1.18 ppm Hydrogen at CH ₃ at position 18: 0.84 ppm By circular dichroism and resolution by X-ray diffraction pattern, the isomer referred to above as B has the configuration 21R. It was determined that the corresponding isomer, also called, corresponds to the configuration 21S. Example 3 [6・7 ³ H]-17β-(2-hydroxy-1-oxopropyl)-17α-methylestra-4・
9-dien-3-one (isomer A and isomer B) Step A: 17α-methyl-17β-(2-iodo-1
-Oxopropyl)estra-5(10)・9(11)-dien-3-one with cyclic [6・7 ³ H]-3-(1・
2-ethanediyl) acetal (mixture of isomers) Proceed as in step A of example 2, except that 17.5 mg of 17α-methyl-17β-(1-oxopropyl)estra-5(10) and 9(11 )-diene-3
Starting from the cyclic [6.7 ³ H]-3-(1.2-ethanediyl) acetal of -one, the desired product is obtained as a resin and used immediately in the next step. Step B: 17α-methyl-17β-(2-acetoxy-1-oxopropyl)estra-5(10)/9(11)
-Dien-3-one cyclic [6.7 ³ H]-3-
(1,2-Ethanediyl)acetal (mixture of isomers) The product obtained in the above step was treated as described in Example 2, Step B, to 1%. Extract with ethyl acetate containing triethylamine. The desired product is obtained and used as such in step C. Step C: [6・7 ³ H]-17β-(2-acetoxy-
Starting from the product obtained above, Step C of Example 2
A resin-like material is obtained according to the same technique as described above, and this is used as it is in the next step. Step D: [6・7 ³ H]-17β-(2-hydroxy-
Example 2 using the tritiated product obtained above
2.64 mg of isomer B (21R) then 1.69 mg of isomer B (21S)
Separate. 17α-Methyl-17β- used at the start of Example 3
(1-oxopropyl)estra-5(10)・9(11)-
Dien-3-one cyclic [6・7 ³ H]-3-(1・
2-ethanediyl) acetal was produced as follows. 23.8 mg of [6・7 ³ H]−17α− under an inert atmosphere.
Methyl-17β-(1-oxopropyl)-estra-4,9-dien-3-one (French patent no.
2374335), 2 c.c. of ethylene glycol containing 1 mg of p-toluenesulfonic acid and 1 c.c.
of ethyl orthoformate. This suspension
Stir at 60 °C for 10 min, add triethylamine, cool, add saturated aqueous sodium bicarbonate solution, extract with ethyl acetate, wash with brine, dry.
Concentrate to dryness under reduced pressure. The product obtained was chromatographed on silica under pressure, 5%. Elute with a benzene/ethyl acetate mixture (9:1) containing triethylamine. Pharmacological studies I Progesterone-like activity of compound A (a) The progesterone-like activity of compound A is JP
J.Ster.Biochem.1975 by Raynaud et al.
6 , 615-622 and Physiology and Genetics.
of Reproduction 1975, Part A, p143−
The study was carried out by the hormone receptor method described in 160. The method is as follows. Sexually immature female rabbits are given 25 μg of estradiol transdermally. Five days after this treatment, the animals are sacrificed and the uterus is removed and homogenized in a buffer of 10 mmol tromethamine, 0.25 molar sutucarose and hydrochloric acid at pH 7.4. The homogenization is performed by centrifugation at 105,000G for 1 hour. Next, the supernatant, ie, the cell sol (cytosol), is adjusted to a dilution of 1/50 (weight/volume). A test tube of the same volume of cytosol was treated with a constant concentration of tritiated 17,21-dimethyl-19-nor-
4,9-pregnadiene-3,20-dione (hereinafter referred to as tritiated compound R) together with increasing concentrations of radioactive 17,21
Incubate at 0°C for 2 hours in the presence or absence of -dimethyl-19-nor-4,9-pregnadiene-3,20-dione (hereinafter referred to as cold compound R), progesterone, or the test compound. The radioactivity of the bound tritiated compound R is determined after 2 and 24 hours by adsorption technique on charcoal/dextran (1.25%-0.625%). Next, (1) a straight line parallel to the abscissa axis and representing the ordinate. (where B _p is the highest amount of bound tritiated compound R measured in an incubator containing only tritiated compound R, and B _nio is the highest amount of bound tritiated compound R measured in an incubate containing tritiated compound and a large excess of cold compound R. is the minimum amount of bound tritiated compound R measured in (2500 10 ^-9 M) and (2) the percentage of bound tritiated compound R as a function of the logarithm of the concentration of added cold compound B/B _p The values CP and CX can be determined by finding the intersection of this straight line I ₅₀ and the above curve. Here, CP represents the immobilization of the tritiated compound R by 50%.
It is the concentration of cold progesterone that inhibits up to. CX fixes tritiated compound R by 50%
This is the concentration of the test compound that inhibits the The relative affinity, or RLA, of the test compound is expressed by the following formula: RLA=100×CP/CX The results obtained are as follows.

[Table] Conclusion Compound A has a much greater affinity for progesterone's specific uterine receptor than progesterone. Therefore, Compound A has very strong progestin-like activity. (b) Progestin-like activity was determined by Clauberg test. According to this test, sexually immature female rabbits in groups of three are presensitized by subcutaneous administration of estradiol at a dose of 5 μg daily for 5 days. After 2 days, they are treated daily for 5 days by subcutaneous route with the test compound. Animals were killed on day 6, and uterine sections were examined to observe the development of a spongy layer of the endometrium, which is characteristic of progesterone-like effects.
Record in units. Compound A was used as a sesame oil solution to which 5% benzyl alcohol was added.

[Table] In this way, at a dosage of 1 μg per day,
2.2 Mac Phail units are obtained. Therefore,
The test compound has very strong progesterone-like activity. Determination of the anti-estrogenic activity of Compound A The anti-estrogenic activity of this compound was determined by Burin
[Endo. 49 , 429 (1951)] and the test of Dorfman et al. [Methods in
Hormone Research. Vol. 118 (1962)] in sexually immature female mice. The estrogen used was estradiol. Groups of 4 female mice, 18 days old, are administered estradiol alone, test compound alone, or estradiol and test compound by subcutaneous injection daily for 3 days. In the latter case, the two steroids are injected at different locations. On the fourth day, mice are sacrificed and their uteri are excised and weighed. Estradiol was administered as a solution in 5% benzyl alcohol in sesame oil at a total dose of 0.27 μg, and each injection was per mouse.
It was carried out in a volume of 0.1 cc. The test compound was used as a solution in sesame oil with 5% benzene alcohol added, and 0.3 μg, 1
Total doses of μg, 3 μg, and 10 μg were administered, and injections were performed in a volume of 0.1 cc per mouse. The results obtained are summarized in the table.

【table】

Table 1 These results thus show that the test compound has clear anti-estrogenic activity with respect to estradiol at a dose of 1 μg.

Claims (1)

[Claims] Linear formula (Here, X represents a hydrogen or tritium atom, R ₁ represents an alkyl group containing 1 to 3 carbon atoms, R ₂ represents an alkyl group containing 1 to 12 carbon atoms, and R ₃ represents an alkyl group containing 1 to 4 carbon atoms) in the form of a 21R or 21S epimer or a mixture of these epimers. 2. A compound of the formula according to claim 1, wherein X represents a hydrogen atom. 3 R ₁ represents a methyl group, and 21R or 21S
Compounds of the formula according to claim 1 or 2 in the form of individual epimers or mixtures of these epimers. 4 R ₂ represents a methyl group, and 21R or 21S
Compounds of the formula according to claim 1, 2 or 3 in the form of each epimer or a mixture of these epimers. 5 R ₃ represents a methyl group, and 21R or 21S
5. Compounds according to any of claims 1 to 4 in the form of individual epimers or mixtures of these epimers. 6. 17α-Methyl-17β-(2-hydroxy-1-oxopropyl)estra-4,9-dien-3-one in the form of each epimer of hydroxyl or a mixture of its epimers A compound according to item 1. 7 In the form of each hydroxyl epimer or a mixture of the epimers [6.7 ³ H]
-17α-methyl-17β-(2-hydroxy-1-
oxopropyl)estra-4,9-diene-3
The compound according to claim 1, which is -one. 8th equation (Here, R ₁ represents an alkyl group containing 1 to 3 carbon atoms, R ₂ represents an alkyl group containing 1 to 12 carbon atoms, and R ₃ represents an alkyl group containing 1 to 4 carbon atoms. A progestin-like and antiestrogenic pharmaceutical composition containing as active ingredient at least one compound in the form of a 21R or 21S epimer (representing an alkyl group containing 21R or 21S) or a mixture of these epimers. 9th equation (Here, R ₁ represents an alkyl group containing 1 to 3 carbon atoms, R ₂ represents an alkyl group containing 1 to 12 carbon atoms, and R ₃ represents an alkyl group containing 1 to 4 carbon atoms. An agent for determining the presence and location of specific receptors for progesterone, consisting of a tritiated compound in the form of a 21R or 21S epimer (representing an alkyl group containing 21R or 21S) or a mixture of these epimers. 10th equation (Here, R ₁ represents an alkyl group containing 1 to 3 carbon atoms, R ₂ represents an alkyl group containing 1 to 12 carbon atoms, and R ₃ represents an alkyl group containing 1 to 4 carbon atoms. 21R or 21S epimer (representing an alkyl group containing) or a mixture of these epimers, the method comprises: (Here, K represents a ketal group, and R ₁ , R ₂ and R ₃ have the above-mentioned meanings) is treated with an oxidizing agent in the presence of a tertiary alcoholate, and then treated with a reducing agent to give the following reaction. formula The compound is obtained as a mixture of 21R and 21S epimers, and the ketal group is hydrolyzed and the △5(10)/9(11) double bond system is isomerized into the △4/9 double bond system. The compound of the corresponding formula is treated as a 21R epimer by the action of an acid hydrolyzing agent that can
A process for the preparation of compounds of the formula, characterized in that they are obtained as a mixture with the 21S epimer and, if desired, separated into each of the epimers. 11th equation (Here, X represents a hydrogen or tritium atom, R ₁ represents an alkyl group containing 1 to 3 carbon atoms, R ₂ represents an alkyl group containing 1 to 12 carbon atoms, and R ₃ represents an alkyl group containing 1 to 4 carbon atoms _. (Here, X, K, R ₁ , R ₂ and R ₃ have the above-mentioned meanings) A strong base is applied to the compound to form an intermediate enolate, which is then reacted with iodine to form the following formula: The compound was obtained as a mixture of 21R isomer and 21S isomer, and this was treated with alkali acetate to form the following formula: was obtained as a mixture of 21R and 21S isomers, and the ketal group was hydrolyzed and △
By acting with an acid hydrolyzing agent that can isomerize the 5(10)/9(11) double bond system into a △4/9 double bond system, the following formula is obtained. The compound of _formula A process for the preparation of compounds of formula I, characterized in that the compounds are obtained as a mixture of 21R and 21S isomers, which, if desired, are separated into each of the epimers.